Sodium Zirconium Cyclosilicate among Individuals with Hyperkalemia: A 12-Month Phase 3 Study

Abstract

Background and objectives: Oral sodium zirconium cyclosilicate (formerly ZS-9) binds and removes potassium via the gastrointestinal tract. Sodium zirconium cyclosilicate-associated restoration and maintenance of normokalemia and adverse events were evaluated in a two-part, open label, phase 3 trial.

Design, setting, participants, & measurements: In the correction phase, adult outpatients with plasma potassium ≥5.1 mmol/L (i-STAT Point-of-Care) received sodium zirconium cyclosilicate 10 g three times daily for 24-72 hours until normokalemic (potassium =3.5-5.0 mmol/L). Qualifying participants entered the ≤12-month maintenance phase and received sodium zirconium cyclosilicate 5 g once daily titrated to maintain normokalemia without dietary or medication restrictions. Prespecified primary end points were restoration of normal serum potassium values (3.5-5.0 mmol/L) during the correction phase and maintenance of serum potassium ≤5.1 mmol/L during the maintenance phase. Adverse events were assessed throughout.

Results: Of 751 participants, 746 (99%) achieved normokalemia during the correction phase (mean serum potassium =4.8 mmol/L; 95% confidence interval, 4.7 to 4.8) and entered the maintenance phase; 466 (63%) participants completed the 12-month trial. Participants were predominantly white, men, and age ≥65 years old; 74% had an eGFR<60 ml/min per 1.73 m², and 65% used renin-angiotensin-aldosterone system inhibitors. Mean time on sodium zirconium cyclosilicate was 286 days. Mean daily sodium zirconium cyclosilicate dose was 7.2 g (SD=2.6). Over months 3-12, mean serum potassium was 4.7 mmol/L (95% confidence interval, 4.6 to 4.7); mean serum potassium values ≤5.1 and ≤5.5 mmol/L were achieved by 88% and 99% of participants, respectively. Of 483 renin-angiotensin-aldosterone system inhibitor users at baseline, 87% continued or had their dose increased; 11% discontinued. Among 263 renin-angiotensin-aldosterone system inhibitor-naïve participants, 14% initiated renin-angiotensin-aldosterone system inhibitor therapy. Overall, 489 (66%) participants experienced adverse events during the maintenance phase, and 22% experienced a serious adverse event. Of eight (1%) deaths, none were considered related to sodium zirconium cyclosilicate. Nine (1%) and 34 (5%) participants experienced serum potassium <3.0 and 3.0-3.4 mmol/L, respectively.

Conclusions: After achieving normokalemia, individualized once daily sodium zirconium cyclosilicate was associated with maintenance of normokalemia without substantial renin-angiotensin-aldosterone system inhibitor changes for ≤12 months.

Keywords: Confidence Intervals; EGFR protein, human; Gastrointestinal Tract; Outpatients; Plasma; Point-of-Care Systems; Potassium; Receptor, Epidermal Growth Factor; Sodium; Zirconium; antibiotic K 4; chronic kidney disease; hyperkalemia; renin angiotensin system; sodium zirconium cyclosilicate (SZC).

Graphical abstract

Figure 1.

(A) Study design and (B) participant disposition. ^aParticipants who achieved normokalemia (potassium [K⁺] =3.5–5.0 mmol/L) as measured by the i-STAT Point-of-Care device at any point during the correction phase were immediately eligible to enter the 12-month maintenance phase and received once daily treatment with sodium zirconium cyclosilicate (SZC; provided in 40 ml of water [no rinse] or 180 ml with 2×30-ml rinses). ^bK⁺ was only measured on days when SZC was administered. ^cOff-drug values were collected 7 (±1) days after the last administration of SZC. Three participants were excluded from serum K+ analyses for the correction phase: two did not have at least one serum K⁺ measurement, and one had a missing K⁺ measurement during active dosing; however, this participant had a postdose K⁺ measurement and was eligible for entry into the maintenance phase.

Figure 2.

Proportion of participants who achieved a potassium (K⁺) value of (A) 3.5–5.0, (B) 3.5–5.5, or (C) >5.0 mmol/L by i-STAT and serum K⁺ during the correction phase (CP) and (D) change in K⁺ from baseline (with annotated mean change and percentage change values) by i-STAT and serum K⁺ during the CP. Data in A and B were calculated using the last observation carried forward method. BL, baseline; 95% CI, 95% confidence interval.

Figure 3.

Proportion of participants with mean serum potassium (K⁺) values (A) ≤5.1, (B) ≤5.5, and (C) 3.5–5.5 mmol/L by visit in the maintenance-phase intention-to-treat (ITT) population; (D) box and whisker plots of median, interquartile range, minimum, and maximum serum K⁺ values at months 3–12, 6–9, and 9–12 in the maintenance-phase ITT population; and (E) mean serum K⁺ over time in the maintenance-phase ITT population. The ITT population included all participants who received sodium zirconium cyclosilicate (SZC) and had any postbaseline K⁺ values measured during the study phase. Gray bars in A–C represent means of all visits occurring over months 3–12. In D, the median serum K⁺ was 5.5 mmol/L at correction-phase (CP) baseline, 4.7 mmol/L from months 3–12 and months 6–9, and 4.6 mmol/L from months 9–12. For all bars in E, P<0.001 versus CP baseline. Off-drug (OD) values were recorded at 7 (±1) days after the last dose of SZC. Δ indicates change; 95% CI, 95% confidence interval.

Figure 4.

Proportion of participants with (A) normal bicarbonate levels and (B) a bicarbonate level <22 mmol/L in the maintenance-phase safety population. Normal bicarbonate levels were defined as 19–34 mmol/L as determined by individual laboratories on the basis of age/sex. The safety population comprised all participants who received one or more doses of sodium zirconium cyclosilicate during the given study phase and had any postbaseline follow-up for safety. CP, correction phase.